Cell motility through plasma membrane blebbing

Abstract

Plasma membrane blebs are dynamic cytoskeleton-regulated cell protrusions that have been implicated in apoptosis, cytokinesis, and cell movement. Influencing Rho-guanosine triphosphatase activities and subsequent actomyosin dynamics appears to constitute a core component for bleb formation. In this paper, we discuss recent evidence in support of a central role of nonapoptotic membrane blebbing for cell migration and cancer cell invasion as well as advances in our understanding of the underlying molecular mechanisms. Based on these studies, we propose that in a physiological context, bleb-associated cell motility reflects a cell's response to reduced substratum adhesion. The importance of blebbing as a functional protrusion is underscored by the existence of multiple molecular mechanisms that govern actin-mediated bleb retraction.

Figure 1.

Molecular requirements for bleb formation and retraction. (A) Schematic presentation of a PM bleb life cycle. Many of the molecular details depicted refer to the scenario in filamin A–deficient M2 melanoma cells (Cunningham, 1995; Charras et al., 2006). Because not all molecular players detected in blebs are directly involved in blebbing and localization of some operating components is not detected upon overexpression of epitope-tagged proteins (Charras et al., 2006; Tournaviti et al., 2007), only components with documented localizations and functional releveance are indicated. Blebbing is initiated by extracellular triggers, causing localized destabilization or depolymerization of the cortical actin meshwork (1). Local disruption of the cortex–membrane interaction leads to the rapid formation of a bulky PM protrusion promoted by the cytoplasmic hydrostatic pressure (cytosolic flow; Trinkaus, 1973). The expanding bleb PM is not coupled to an actin cortex but is coated by actin–membrane cross-linker proteins of the ERM family such as ezrin (2). Actin is subsequently polymerized at the bleb cortex (3) by mechanisms that are still unknown, leading to a halt in bleb expansion (static phase). Increased actin filament assembly, recruitment of myosin to the bleb lumen, and local activity of RhoA-ROCK generate contractility that consequently retracts the bleb (4; Cunningham, 1995; Sheetz et al., 2006; Charras et al., 2007). (B) Maximum projection from confocal z stacks of a GFP-RhoA-V14 (green) expressing the MDA-MB-435 tumor cell contacting matrigel. The cell shows numerous PM blebs with constitutively active RhoA (RhoA-V14) partially visible in the bleb cortex. Filamentous actin was visualized using rhodamine-phalloidin (red). Bar, 20 μm.